2. Academic Validation
  3. Discovery of Aryl Benzoyl Hydrazide Derivatives as Novel Potent Broad-Spectrum Inhibitors of Influenza A Virus RNA-Dependent RNA Polymerase (RdRp)

Discovery of Aryl Benzoyl Hydrazide Derivatives as Novel Potent Broad-Spectrum Inhibitors of Influenza A Virus RNA-Dependent RNA Polymerase (RdRp)

  • J Med Chem. 2022 Mar 10;65(5):3814-3832. doi: 10.1021/acs.jmedchem.1c01257.
Xinjin Liu 1,  Jinsen Liang 2,  Yongshi Yu 2,  Xin Han 2,  Lei Yu 1,  Feifei Chen 1,  Zhichao Xu 2,  Qi Chen 1,  Mengyu Jin 2,  Chune Dong 2,  Hai-Bing Zhou 2 3,  Ke Lan 1,  Shuwen Wu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 2 Frontier Science Center for Immunology and Metabolism, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
  • 3 Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
PMID: 35212527 DOI: 10.1021/acs.jmedchem.1c01257
Abstract

Influenza A viruses possess a high antigenic shift, and the approved anti-influenza drugs are extremely limited, which makes the development of novel anti-influenza drugs for the clinical treatment and prevention of influenza outbreaks imperative. Herein, we report a series of novel aryl benzoyl hydrazide analogs as potent anti-influenza agents. Particularly, analogs 10b, 10c, 10g, 11p, and 11q exhibited potent inhibitory activity against the avian H5N1 flu strain with EC50 values ranging from 0.009 to 0.034 μM. Moreover, compound 11q exhibited nanomolar Antiviral effects against both the H1N1 virus and Flu B virus and possessed good oral bioavailability and inhibitory activity against influenza A virus in a mouse model. Preliminary mechanistic studies suggested that these compounds exert anti-influenza virus effects mainly by interacting with the PB1 subunit of RNA-dependent RNA polymerase (RdRp). These results revealed that 11q has the potential to become a potent clinical candidate to combat seasonal influenza and influenza pandemics.

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